ubiquinone and cerivastatin

Endothelial dysfunction (ED) is the functional prestep in atherosclerosis. Aim of the present study was to evaluate the effects of a potent antioxidant (coenzyme Q(10), CoQ(10)) and of cerivastatin on ED of the brachial artery.. Twenty-five male patients with manifest ED (flow-mediated vasodilation [FMD%]<4.5%) were included in this prospective, randomized, cross-over study. ED of the brachial artery was assessed by the use of high-resolution ultrasound. Each patient had to pass through three treatment phases ((1) single therapy with cerivastatin (C), (2) single therapy with CoQ(10), (3) combination therapy). FMD% significantly improved throughout all treatment phases ((1) 3.50+/-4.05% vs. 8.80+/-6.39%, p=0.009; (2) -0.25+/-4.0% vs. 7.06%+/-4.39%, p=0.004; (3) 3.14+/-3.54% vs. 8.82+/-5.78%, p=0.011). C led to a significant decrease of CoQ(10) plasma levels (1.23+/-0.34 vs. 0.87+/-0.39 microg/ml, p=0.004).. Our results indicate a positive influence of CoQ(10) supplementation on human ED, which appears to be independent of lipid lowering. Although large-scale studies evaluating other antioxidants failed to demonstrate a positive prognostic effect, Q(10) has never been evaluated in larger trials. Experimental as well as clinical results indicate that CoQ(10) warrants further attention in atherosclerosis research.

Topics: Adult; Aged; Antioxidants; Brachial Artery; Coenzymes; Cross-Over Studies; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Prospective Studies; Pyridines; Stereoisomerism; Ubiquinone; Ultrasonography; Vasodilation

As a class, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors can potentially cause skeletal myopathy. One statin, cerivastatin, has recently been withdrawn from the market due to an unacceptably high incidence of rhabdomyolysis. The mechanism underlying statin-induced myopathy is unknown. This paper sought to investigate the relationship among statin-induced myopathy, mitochondrial function, and muscle ubiquinone levels. Rats were administered cerivastatin at 0.1, 0.5, and 1.0 (mg/kg)/day or dose vehicle (controls) by oral gavage for 15 days. Samples of type I-predominant skeletal muscle (soleus) and type II-predominant skeletal muscle [quadriceps and extensor digitorum longus (EDL)], and blood were collected on study days 5, 10, and 15 for morphological evaluation, clinical chemistry, mitochondrial function tests, and analysis of ubiquinone levels. No histological changes were observed in any of the animals on study days 5 or 10, but on study day 15, mid- and high-dose animals had necrosis and inflammation in type II skeletal muscle. Elevated creatine kinase (CK) levels in blood (a clinical marker of myopathy) correlated with the histopathological diagnosis of myopathy. Ultrastructural characterization of skeletal muscle revealed disruption of the sarcomere and altered mitochondria only in myofibers with degeneration, while adjacent myofibers were unaffected and had normal mitochondria. Thus, mitochondrial effects appeared not to precede myofiber degeneration. Mean coenzyme Q9 (CoQ9) levels in all dose groups were slightly decreased relative to controls in type II skeletal muscle, although the difference was not significantly different in most cases. Mitochondrial function in skeletal muscle was not affected by the changes in ubiquinone levels. The ubiquinone levels in high-dose-treated animals exhibiting myopathy were not significantly different from low-dose animals with no observable toxic effects. Furthermore, ubiquinone levels did not correlate with circulating CK levels in treated animals. The results of this study suggest that neither mitochondrial injury, nor a decrease in muscle ubiquinone levels, is the primary cause of skeletal myopathy in cerivastatin-dosed rats.

Topics: Animals; Drug Evaluation, Preclinical; Female; Mitochondria, Muscle; Muscle, Skeletal; Muscular Diseases; Pyridines; Rats; Rats, Sprague-Dawley; Ubiquinone

Cerivastatine was administered as a reversible HMG-CoA reductase inhibitor (statine) to treat hypercholesterolemia until its withdrawal from the market following 52 reports of death due to drug-related rhabdomyolysis and acute renal failure. In most cases, cerivastatine was applied in combination with drugs which influenced the liver metabolism of cerivastatine via cytochromeoxidase P 450 isoenzymes. We report a well-documented case of acute rhabdomyolysis following cerivastatine monotherapy. The diagnosis was confirmed additionally by muscle biopsy.Finally,we give an overview of the current knowledge concerning therapy with HMG-CoA reductase inhibitors,1 year after the withdrawal of cerivastatine from the market.

Topics: Acute Disease; Anticholesteremic Agents; Aryl Hydrocarbon Hydroxylases; Biopsy; Coenzymes; Comorbidity; Creatine Kinase; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diagnosis, Differential; Drug Interactions; Electromyography; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver Cirrhosis, Alcoholic; Liver Function Tests; Middle Aged; Muscle, Skeletal; Neurologic Examination; Pancreatic Diseases; Pyridines; Rhabdomyolysis; Stomach Neoplasms; Ubiquinone

The oxidative modification of low density lipoprotein (LDL) is thought to play an important role in atherogenesis. Drugs of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) family are usually used as a very effective lipid-lowering preparations but they simultaneously block biosynthesis of both cholesterol and ubiquinone Q10 (coenzyme Q), which is an intermediate electron carrier in the mitochondrial respiratory chain. It is known that reduced form of ubiquinone Q10 acts in the human LDL as very effective natural antioxidant. Daily per os administration of HMG-CoA reductase inhibitor simvastatin to rats for 30 day had no effect on high-energy phosphates (adenosin triphosphate, creatine phosphate) content in liver but decreased a level of these substances in myocardium. We study the Cu2+-mediated susceptibility of human LDL to oxidation and the levels of free radical products of LDL lipoperoxidation in LDL particles from patients with atherosclerosis after 3 months treatment with natural antioxidants vitamin E as well as during 6 months administration of HMG-CoA reductase inhibitors such as pravastatin and cerivastatin in monotherapy and in combination with natural antioxidant ubiquinone Q10 or synthetic antioxidant probucol in a double-blind placebo-controlled trials. The 3 months of natural antioxidant vitamin E administration (400 mg daily) to patients did not increase the susceptibility of LDL to oxidation. On the other hand, synthetic antioxidant probucol during long-time period of treatment (3-6 months) in low-dose (250 mg daily) doesn't change the lipid metabolism parameters in the blood of patients but their high antioxidant activity was observed. Really, after oxidation of probucol-contained LDL by C-15 animal lipoxygenase in these particles we identified the electron spin resonance signal of probucol phenoxyl radical that suggests the interaction of LDL-associated probucol with lipid radicals in vivo. We observed that 6 months treatment of patients with pravastatine (40 mg daily) or cerivastatin (0.4 mg daily) was followed by sufficiently accumulation of LDL lipoperoxides in vivo. In contrast, the 6 months therapy with pravastatin in combination with ubiquinone Q10 (60 mg daily) sharply decreased the LDL initial lipoperoxides level whereas during treatment with cerivastatin in combination with probucol (250 mg daily) the LDL lipoperoxides concentration was maintained on an invariable level. Therefore, antioxida

Topics: Animals; Antioxidants; Arteriosclerosis; Coenzymes; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipid Peroxidation; Lipoproteins, LDL; Liver; Male; Middle Aged; Oxidation-Reduction; Pravastatin; Probucol; Pyridines; Rats; Time Factors; Ubiquinone; Vitamin E

Inhibitors of the key enzyme of cholesterol biosynthesis beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (statins) decrease cholesterol content in atherogenic low-density lipoproteins in patients with coronary heart disease and hypercholesterolemia, but inhibited biosynthesis of ubiquinone Q10 protecting low-density lipoproteins from free radical oxidation. Cerivastatin in a daily dose of 0.4 mg markedly increased the content of lipid peroxides in low-density lipoproteins. However, complex therapy with cerivastatin and antioxidant probucol (250 mg/day) was accompanied by a sharp decrease in the content of lipid peroxides in low-density lipoproteins in patients with coronary heart disease in vivo. These data indicate that antioxidant agents should be used in combination with inhibitors of beta-hydroxy-beta-methylglutaryl-coenzyme A reductase (hypolipidemic preparations) for the therapy of patients with coronary heart disease.

Topics: Antioxidants; Cholesterol; Cholesterol, LDL; Coenzymes; Double-Blind Method; Enzyme Inhibitors; Free Radicals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Lipoproteins, LDL; Male; Middle Aged; Myocardial Ischemia; Oxygen; Peroxides; Placebos; Probucol; Pyridines; Random Allocation; Time Factors; Ubiquinone

Topics: Cardiovascular Diseases; Cholesterol; Coenzymes; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyridines; Rhabdomyolysis; Ubiquinone; United States; United States Food and Drug Administration